In normal tissue there is an equilibrium between synthesis and degradation. Extracellular matrix is degraded by proteases which belong to at least three groups of matrix metalloproteases. These are the collagenases, gelatinases and stromelysins. Normally there are specific inhibitors for these catabolic enzymes such as xcex12 macroglobulines and MMP (=tissue inhibitor of metalloproteases (MMP)) so that an excessive degradation of extracellular matrix does not occur. A related group of proteases is the adamalysins. A prominent member of the adamalysins is TACE (TNF-xcex1-converting enzyme).
At least 11 different and yet highly homologous MMP species have been characterized, including the interstitial fibroblast collagenase (MMP-1, HFC), the neutrophil collagenase (MMP-8, HNC), two gelatinases, stromelysins (such as HSL-1) and HPUMP (for a recent review, see Birkedal-Hansen, H., Moore, W. G. I., Bodden, M. K, Windsor, L. J., Birkedal-Hansen; B., DeCarlo, A., Engler, J. A., Critical Rev. Oral Biol. Med. (1993) 4, 197-250. These proteinases share a number of structural and functional features but differ somewhat in their substrate specificity. Only HNC and HFC are capable of cleaving type I, II and III native triple-helical collagens at a single bond with the production of fragments xc2xe and xc2xc of the native chain length. This lowers the collagen melting point and makes them accessible to further attack by other matrix degrading enzymes.
However, the uncontrolled excessive degradation of this matrix is a characteristic of many pathological states such as e.g. in the clinical picture of rheumatoid arthritis, osteoarthritis, multiple sclerosis, in the formation of tumour metastases, corneal ulceration, inflamative diseases and invasion and in diseases of the bone and teeth.
It can be assumed that the pathogenesis of these clinical pictures can be favourably influenced by the administration of matrix metalloprotease inhibitors. A number of compounds in the meantime are known in the literature (see e.g. the review article of Nigel R A Beeley et al. Curr. Opin. ther. Patents 4 (1), 7 (1994)) or are described in the patent literature, these mainly being peptides with a hydroxamic acid residue, a thiol or phosphine group as a zinc binding group (see e.g. WO-A-9209563 by Glycomed, EP-A-497 192 by Hoffmann-LaRoche, WO-A-9005719 by British Biotechnology, EP-A489 577 by Celltech, EP-A-320 118 by Beecham, U.S. Pat. No. 4,595,700 by Searle among others).
Some of these compounds have a high activity as inhibitors of matrix metalloproteases but only have a very low oral availability.
It has now been found that the claimed new barbituric acid derivatives are very efficacious as matrix metallo-protease inhibitors and have a good oral availability.
The present invention therefore concerns substances of the general formula I 
in which
X, Y and Z are independently of one another oxygen, sulphur or NH,
R1 represents a group Wxe2x80x94V
W is a valence dash or a straight-chained or branched C1-C8 alkyl or a C2-C8 alkenyl group which is optionally once or several times substituted,
V is an optionally substituted monocycle or bicycle which can contain one or several heteroatoms, or
Wxe2x80x94V is a C1-C20 akyl group which can be interrupted by heteroatoms, one or several carbon atoms are optionally substituted,
R2 and R3 represent hydrogen or one of the two represent lower alkyl or lower acyl
R4 and R5 denote independently of each other for Axe2x80x94D wherein A represents a dash alkyl, alkenyl, acyl, alkylsulfonyl, sulfonyl, alkylaminocarbonyl, aminocarbonyl, alkoxycarbonyl, oxy-carbonyl, alkylaminothiocarbonyl, aminothio-carbonyl which is optionally once or several times substituted.
D represents a hydrogen, mono or bicycle, the monocycle or bicycle is optionally once or several times interrupted by heteroatoms and the monocycle or bicycle is once or several times substituted, or
R4 and R5 together with the nitrogen atom to which they are bound represent a ring which optionally can be interrupted by a further N atom, said ring can be condensed to a monocycle or bicycle, said ring can optionally be substituted once or several times independently by the residues hydroxy, alkoxy, amino, alkylamino, dialkylamino, nitril or by Exe2x80x94G wherein E represents a dash alkyl, alkenyl, acyl, alkylsulfonyl, sulfonyl, alkylaminocarbonyl, aminocarbonyl, alkoxycarbonyl oxycarbonyl, alkylaminothiocarbonyl, aminothiocarbonyl which is optionally substituted; G represents a hydrogen, mono or bicycle, the monocycle or bicycle is optionally once or several times interrupted by heteroatoms and the monocycle or bicycle is once or several times substituted,
pharmacologically acceptable salts or prodrugs thereof as well as the use of these compounds to produce pharmaceutical agents.
The monocycle listed in the case of R1, R4 and R5 is understood as saturated or unsaturated ring systems with 3-8, preferably 5-7 carbon atoms which can optionally be interrupted one or several times by heteroatoms such as nitrogen, oxygen or sulphur in particular a cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl residue. Lower alkyl, alkoxy and halogen come above all into consideration as substituents.
The bicycle listed under R1, R4 and R5, is understood to be a condensed bicycle or a bicycle of the type monocycle1-L-monocycle2, wherein L denotes a valence dash C1-C4-alkyl group, C2-C4 an alkenyl group, an oxygen or xe2x80x94C(O)xe2x80x94 group.
The bicycle is preferably a residue such as a naphthyl, tetrahydronaphthyl dekalinyl, quinolinyl, isoquinolinyl, tetrahydroquino-linyl, tetrahydroisoquinolinyl, indolyl, benzimidazoyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxazolyl, purinyl, biphenyl or (4-phenoxy)phenyl residue and in particular a naphthyl, biphenyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, indolyl or benzimidazolyl residue.
The residues listed under R1, R4 and R5 can optionally be substituted once or several times by halogen, hydroxy, thio, alkyl, hydroxyalkyl, alkoxy, alkylthio, alkylsulfinyl, alkyl-sulfonyl, amino, alkylamino, dialkylamino, nitro, carboxyl, carboxamido, alkoxycarbonyl, amino or aminocarbonyl optionally substituted once or twice by lower alkyl, nitrile, oxo, thiocarboxamido, alkoxythiocarbonyl, alkmercaptocarbonyl, phosphono, alkylphosphono, dialkylphosphono, alkylsulfonylamido, arylamino, aryl, hetaryl, aryloxy, arylthio, arylsulfinyl, arylsulfonyl or acyl.
In this case the halogen, hydroxy, oxo, thio, alkoxy, alkylthio, amino, aminocarbonyl, carboxyl and acyl groups are preferred.
Lower alkyl denotes C1-C6-Alkyl, preferred methyl, ethyl, propyl, isopropyl or tert.-butyl.
Lower acyl in the residues R2 and R3 above all denotes for xe2x80x94C(O)xe2x80x94C1-C6-alkyl or xe2x80x94C(O)H, preferred for an acetyl group.
The alkyl residues in R1, R4 and R5 can optionally be interrupted once or several time by heteroatoms (O, S, NH).
Alkyl in the residues R4 and R5 denotes as such or in combination with alkoxy, alkylthio, arylsulfonyl, alkylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylamino, alkoxycarbonyl, aryloxycarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl a straight-chained, branched, saturated or unsaturated residue with 1-11, preferably 1-8 carbon atoms such as e.g. a methyl, ethyl, propyl, pentyl, octyl, allyl, propargyl, 2,4-pentadienyl, isopropyl, sec. butyl, 3-methylbutyl, 2-hydroxyhexyl and in particular a methyl, propyl, isopropyl, pentyl, octyl, allyl, 3-methylbutyl, 2-hydroxyhexyl and propargyl residue.
Aryl, also in combination with aryloxy, arylthio, arylsulfonyl, arylaminocarbonyl, aryloxycarbonyl, arylaminothiocarbonyl is understood as a phenyl or naphthyl residue which can optionally be substituted in particular by halogen, lower alkyl or alkoxy.
The C1-C20 alkyl group listed for R1 is a straight-chained or branched saturated residue such as e.g. a methyl, ethyl, propyl, butyl, pentyl, octyl, decyl, undecyl, isobutyl, 3-methylbutyl or 7-methyloctyl group. Hydroxy and amino residues come above all into consideration as substituents. The alkyl chains can be interrupted once or several times by oxygen, nitrogen or sulphur. The preferred heteroatom interruption is oxygen (ether linkage) or xe2x80x94C(O)NHxe2x80x94 (amid linkage). The most preferred heteroatom interrupted residues are xe2x80x94(CH2CH2O)nxe2x80x94(CH2)mH and n=2 or 3 and m=1 or 2.
W of R1 is preferrably a methyl, ethyl, butyl or hexyl residue; V is in particular a phenyl, Pyridyl, imidazolyl residue which can optionally be substituted above all by lower alkyl, hydroxy, alkoxyamid, sulfonamide or halogen. The most preferred R1 residues are C6-C12-Alkyl residue or a xe2x80x94(CH2)nxe2x80x94C6H4xe2x80x94(CH2)mH residue, wherein m and n are equal or less than 8, the (CH2)-group is optionally interrupted by oxygen, sulfur, or NH and one or two carbons of the phenyl ring are substituted for N-heteroatoms. The alkyl, aryl, hetaryl groups are optionally substituted by small polar substituents.
The most preferred R1 residues are n-Octyl, n-Decyl, Biphenyl or octyl or decyl type residues showing two or three oxygen heteroatoms like 2-(2-(2-methoxyethoxy)ethoxy)ethyl 2-(2-ethoxyethoxy)ethyl or biphenyl-type residues showing one or two nitrogen heteroatoms. The bridging monocycle is optionally ortho substituted and the terminal monocycle of the biphenyl or biphenyl type residue is optionally ortho or para substituted by a small, polar substituent like NH2, xe2x80x94NO2, xe2x80x94SO2NH2, SO2CH3, Acetyl, Hydroxy, Methoxy, Ethoxy or Nitril-group. The para substitution of the terminal monocycle is more preferred.
Halogen is understood as chlorine, bromine, iodine and preferably chlorine.
The hetaryl residues listed for R4 and R5 denote preferred for a pyridine, pyrazine, piperazine, imidazole, thiazole, thiophene or indole ring preferably a pyridine, imidazole and thiophene ring.
The acyl residue listed for the residues R4 and R5 is a residue with 1-10, preferably 6-8 carbon atoms such as e.g. a hexanoyl or octanoyl residue. The alkyl group can be interrupted once or several times by heteroatoms or heteroatom groups like S, O, NH, SO2, amido or carbonyl. These residues can be substituted by amino groups, alkyl groups, aryl groups, arylalkyl groups, alkylamino groups, dialkylamino groups, alkoxy groups and aromatic compounds. These are then amino acid residues preferably a phenylalanine and tryptophan residue in this case.
If R4 and R5 form a ring together with the nitrogen atom to which they are bound, these are 5-7-membered rings preferably a six-membered ring. The piperidine, piperazine, tetrahydroquinoline and tetrahydroiso-quinoline, bicyclo(9.4.0)pentadecyl and 1,2,3,4-tetrahydrobenzo(g)isoquinoline rings are preferred.
If compounds of the general formula I contain one or several asymmetric carbon atoms, the optically active compounds of the general formula I are also a subject matter of the present invention.
Independently of each other the preferred meaning for X, Y, Z is oxygen, for R2 and R3 it is hydrogen. A more preferred combination is X, Y and Z equal each oxygen and R2 is identical to R3 and both mean hydrogen.
It is also preferred that R4 and R5 do not both represent hydrogen.
The term xe2x80x9cseveralxe2x80x9d means in connection with heteroatoms in monocycles or bicycles preferred one, two or three more preferred one or two, the most preferred heteroatom is nitrogen.
The term xe2x80x9cseveralxe2x80x9d means in connection with substituents or substitution preferred one to five, more preferred one, two or three most preferred one or two.
The term xe2x80x9cheteroatomxe2x80x9d in connection with alkyl or acyl groups means preferred oxygen or NH, more preferred oxygen.
Substitutions of monocycles or bicycles in R1, R4 and R5 are halogen, nitro, hydroxy, alkoxy, amino, alkylamino, dialkylamino, halogenmethyl, dihalogenmethyl, trihalogenmethyl, phosphono, alkylphosphono, dialkylphosphono, SO2NH2, SO2NH(alkyl), SO2N(alkyl)2, SO2(alkyl), acetyl, formyl, nitril, COOH, COOalkyl, xe2x80x94OC(O)alkyl, xe2x80x94NHC(O)Oalkyl, OC(O)O-aryl, xe2x80x94NHC(S)NH2, xe2x80x94NHC(S)NHalkyl, xe2x80x94NHC(O)-aryl.
The preferred ring structure formed together with the nitrogen R4 and R5, is piperazin or piperidin, both of which are substituted preferrably at the 4-position. In the case of piperidin the 4 position is optionally substituted by a second substitute hydroxy, amino, alkylamino, alkylamino, dialkylamino or alkoxy. The 4 position of piperidin may also form a double bond with the substituent of the 4 position
Preferred substitution of the 4 position of piperidin or piperazin are 6-membered aromatic monocycles which are more preferred substituted in para position by small polar substitutions as hydroxy, lower alkoxy, amino, lower alkylamino, lower dialkylamino, nitro, nitrilo, SO2NH2, SO2NH lower alkyl, SO2 lower alkyl. The 6 membered aromatic monocycle is preferrably bound to the 4 position via a valence bond or a lower alkyl spacer.
In the case that R4 is hydrogen a lower alkyl a lower alkylaryl, then R5 is preferred a acyl derivate preferrably substituted with a monocyle or lower alkylaryl; or a xe2x80x94CHR50xe2x80x94CHR51xe2x80x94NR52xe2x80x94R53 wherein R50 and R51 denote independently of each other for hydrogen, lower alkyl a lower alkoxy. R52 denotes for hydrogen or lower alkyl, R53 denotes a 6-membered aromatic monocycle which is optionally once or several times substituted and bound to the nitogen preferrably via a valence bond or a lower alkyl spacer.
The most preferred combination of meanings in general formula I are
X equals Y equals Z equals oxygen and
R2 equals R3 equals hydrogen and
R1 equals n-Octyl, n-Decyl, Biphenyl or octyl or decyl type residues showing two or three oxygen heteroatoms like 2-(2-(2-methoxyethoxy)-ethoxy)ethyl, 2-(2-ethoxyethoxy)ethyl or biphenyl-type residues showing one or two nitrogen heteroatoms; wherein the bridging monocycle is optionally ortho substituted and the terminal monocycle of the biphenyl or biphenyl type residue is optionally ortho or preferred para substituted by a small, polar substituent like NH2, xe2x80x94NO2, xe2x80x94SO2NH2, SO2CH3, Acetyl, Hydroxy, Methoxy, Ethoxy or Nitril-group and
R4 and R5 form together with the nitrogen to which they are bound a piperazin or piperidin both of which are substituted in the 4 position with a phenyl, pyridyl or pyrazidy ring which is preferred para substituted by a small polar substituent; in the case of piperidin the 4 position may be additionally substituted by hydroxy, lower alkoxy, nitril or amin which may be mono- or disubstituted by lower alkyl.
Compounds of the general formula I can be synthesized by well-known processes preferably in that
a) compounds of the general formula II 
xe2x80x83in which X, Y, Z, R1, R2 and R3 have the above-mentioned meanings and T represents a leaving group such as Hal or OSO2R6.Hal denoting chlorine, bromine or iodine and R6 denoting an aryl or a methyl residue, are reacted with a compound of the general formula III 
xe2x80x83in which R4 and R5 have the meanings stated above and optionally converted into pharmacologically acceptable salts or
b) compounds of the general formula IV 
xe2x80x83in which R1, R4 and R5 have the above-mentioned meanings, Y and Z independently of one another represent oxygen, sulphur or a NH group and R7=methyl, ethyl or phenyl, is reacted with a compound of the general formula V 
xe2x80x83in which R2, R3 and X have the above-mentioned meanings and optionally converted into pharmacologically acceptable salts or
n the case that R4 and/or R5 represent an acyl, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminothiocarbonyl or arylaminothiocarbonyl residue
c) a compound of the general formula VI 
xe2x80x83in which X, Y, Z, R1, R2 and R3 have the above-mentioned meanings, is reacted with a compound of the general formula VII or VIII
R8xe2x80x94Dxe2x80x94Hal (VII) R8Nxe2x95x90Cxe2x95x90Axe2x80x83xe2x80x83(VIII)
xe2x80x83in which R8 re an optionally substituted alkyl or aryl residue, Dxe2x95x90C(O), Oxe2x80x94C(O), SO2 or a valency dash, Hal=chlorine, bromine or iodine and A represents oxygen or sulphur
and optionally converted into pharmacologically acceptable salts.
Compounds of the general formula II are known in the literature. Thus for example 2,4,6-pyrimidine triones brominated in the 5-position can be synthesized by reacting the appropriate bromomalonic acid diakyl esters with urea (e.g. Acta Chim. Acad. Sci. Hung. 107 (2), 139 (1981)). The corresponding brominated or chlorinated compounds of the general formula II can be obtained by reacting 2,4,6-pyrimidine-triones substituted by R1 in the 5-position with bromine (analogous to J. pr. Chemie 136, 329 (1933) or J. Chem. Soc. 1931, 1870) or sulfuryl chloride (J. Chem. Soc. 1938, 1622). In the same manner one can synthesize the 2-imino-4,6-pyrimidine-diones of the general formula II correspondingly halogenated in the 5-position analogously to Collect. Czech. Comm. 48 (1), 299 (1933). The reaction of 2-thia-4,6-pyrimidine-diones substituted by R1 in the 5-position with bromine in glacial acetic acid (analogous to Am. Chem. J. 34, 186) leads to the compounds of the general formula II correspondingly brominated in the 5-position.
Amines of the general formula III are commercially available or are usually known in the literature.
Compounds of the general formula IV are reacted according to known methods with ureas (see for example J. Med. Chem. 10, 1078 (1967) or Helvetica Chim. Acta 34, 459 (1959) or Pharmacie 38 (1), 65 (1983)), thioureas (see for example Indian J. Chem. 24 (10), 1094 (1985) or J. Het. Chem. 18 (3), 635 (1981)) or guanidines (see for example Collect. Czech. Chem. Comm. 45 (12), 3583 (1980)) of the general formula V.
The reactions are usually carried out in an alcohol such as methanol, ethanol or butanol in the presence of an appropriate sodium alcoholate at temperatures between 40xc2x0 C. and 100xc2x0 C. and in the case of the guanidines also at temperatures of up to 200xc2x0 C. (under pressure). In the case of the thioureas the process is frequently carried out in the presence of acetyl chloride (also as a solvent).
Compounds of the general formula IV are known from the literature or can be produced according to processes known from the literature. They can be synthesized for example by weak acidic hydrolysis of the corresponding bislactim ethers (see J. Chem. Soc. Chem. Comm. 5, 400 (1990)). Other methods of synthesis are for example described in Farmaco Ed. Sci. 31 (7), 478 (1976) or Aust. J. Chem., 23 (6), 1229 (1970).
Ureas, thioureas and guanidines of the general formula V are commercially available.
Compounds of the general formula VI can easily be synthesized by reacting an appropriate substituted acetamidomalonic ester according to process b) and subsequent hydrolytic cleavage of the acetyl group (see Can. J. Chem. 42 (3), 605 (1964)).
Carboxylic acid chlorides of the general formula VII are known or can be synthesized by generally known methods from the corresponding carboxylic acids. The reaction is usually carried out with thionyl chloride or phosphorus tribromide or phosphorus pentabromide or pentachloride in inert solvents such as dichloromethane, diethyl ether, dioxane or tetrahydrofuran at temperatures of 0xc2x0 C. to 50xc2x0 C., preferably between 20xc2x0 C. and 40xc2x0 C.
Chloroformic acid esters of the general formula VII are known in the literature or can be obtained by generally known methods from the corresponding alcohols by reaction with phosgene or diphosgene. The reaction proceeds in inert solvents such as e.g. diethyl ether, dichloromethane, dioxane, tetrahydrofuran or toluene at temperatures between xe2x88x9220xc2x0 C. and 20xc2x0 C. In the case of phosgene the reaction is carried out in the presence of bases, usually tertiary amines such as e.g. triethylamine or pyridine.
Sulfonic acid chlorides of the general formula VII are known or can be synthesized analogously to described methods from the corresponding sulfonic acids by reaction with phosphorus pentachloride or thionyl chloride. The reaction is usually carried out in an inert solvent such as e.g. dimethylformamide or also without a solvent at temperatures of 20xc2x0 C. to 180xc2x0 C., preferably at 50xc2x0 C. to 100xc2x0 C.
Isocyanates of the general formula VIII are known or can be synthesized by methods known in the literature. Thus for example appropriate alkyl halogenides of the general formula R8xe2x80x94Hal can be reacted with potassium cyanate analogously to Synthesis 1978, 760. Further methods are to react an acid amide of the general formula R8xe2x80x94CONH2 with oxalyl chloride, to thermally decompose an acid azide of the general formula R8xe2x80x94CON3 or to react an amine of the general formula R8xe2x80x94NH2 with phosgene (analogously to Ann. Chem. 562, 110).
Isothiocyanates of the general formula VIII are known in the literature or can be synthesized analogously to known processes. An amine of the genes formula R8xe2x80x94NH2 is preferably allowed to react with carbon disulphide under alkaline conditions analogously to Chem. Ber. 74, 1375.
The reaction of carboxylic acid halogenides, sulfonic acid halogenides or chloroformic acid esters of the general formula VII with amines of the general formula VI is usually carried out in a solvent such as dichloromethane, dimethylformamide or pyridine with addition of an auxiliary base such as triethylamine or 4-diethylaminopyridine at a temperature between xe2x88x9210xc2x0 C. and 50xc2x0 C., preferably at room temperature.
Compounds of the general formula I can contain one or several chiral centres and can then be present in a racemic or in an optically active form. The racemates can be separated according to known methods into the enantiomers. Preferably diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or with an optically active amine such as e.g. D- or L-xcex1-phenyl-ethylamine, ephedrine, quinidine or cinchonidine.
Alkaline salts, earth alkaline salts like Ca or Mg salts, ammonium salts, acetates or hydrochlorides are mainly used as pharmacologically acceptable salts which are produced in the usual manner e.g. by tritrating the compounds with inorganic or organic bases or inorganic acids such as e.g. sodium hydroxide, potassium hydroxide, aqueous ammonia, C1-C4-alkyl-amines such as e.g. triethylamine or hydrochloric acid. The salts are usually purified by reprecipitation from water/acetone.
The new substances of formula I and salts thereof according to the invention can be administered enterally or parenterally in a liquid or solid form. In this connection all the usual forms of administration come into consideration such as for example tablets, capsules, coated tablets, syrups, solutions, suspension etc. Water which contains additives such as stabilizers, solubilizers and buffers that are usual in injection solutions is preferably used as the injection medium.
Such additives are e.g. tartrate and citrate buffer, ethanol complexing agents (such a ethylenediaminetetra-acetic acid and non-toxic salts thereof), high-molecular polymers (such as liquid polyethylene oxide) to regulate viscosity. Liquid carrier substances for injection solutions have to be sterile and are preferably dispensed into ampoules. Solid carrier substances are e.g. starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, higher molecular fatty acids (such as stearic acid), gelatins, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers (such as polyethylene glycols); suitable preparations for oral application can optionally also contain flavourings and sweeteners.
The dosage can depend on various factors such as manner of administration, species, age and/or individual state of health. The doses to be administered daily are about 10-1000 mg/human, preferably 100-500 mg/human and can be taken singly or distributed over several administrations.
Prodrugs of the compounds of the invention are such which are converted in vivo to the pharmacological active compound. The most common prodrugs are carboxylic acid esters.
Within the sense of the present invention the following barbituric acid derivatives are preferred in addition to the compounds mentioned in the examples and compounds that can be derived by combining all meanings of substituents mentioned in the claims:
1. 5-(N-benzyl-N-octyl)-5-phenyl-barbituric acid
2. 5-(N-benzyl-N-phenethyl)-5-phenyl-barbituric acid
3. 5-(N-benzyl-N-[2-(4-pyridyl)ethyl)]-5-phenyl-barbituric acid
4. 5-(N-benzyl-N-[2-(3-pyridyl)ethyl]-5-phenyl-barbituric acid
5. 5-(N-benzyl-N-[2-(2-pyridyl)ethyl]-5-phenyl-barbituric acid
6. 5-(N-benzyl-N-[2-(2-thiophenyl)ethyl]-5-phenyl-barbituric acid
7. 5-[N-(3-methylbutyl)-N-(3-phenylpropyl)]-5-phenyl-barbituric acid
8. 5-(N-benzyl-N-[3-(4-pyridyl)propyl])-5-phenyl-barbituric acid
9. 5-(N-benzyl-N-[2-(2-imidazolyl)ethyl])-5-phenyl-barbituric acid
10. 5-(N-benzyl-N-[2-(1-imidazolyl)ethyl])-5-phenyl-barbituric acid
11. 5-(N-butyl-N-phenylalaninyl)-5-phenyl-barbituric acid
12. 5-(N-butyl-N-tryptophanyl)-5-phenyl-barbituric acid
13. 5-(N-benzyl-N-cyclohexyl)-5-phenyl-barbituric acid
14. 5-[N-benzyl-N-(2-pyridyl)]-5-phenyl-barbituric acid
15. 5-[N-butyl-N-(4-piperidinyl)]-5-phenyl-barbituric acid
16. 5-[N-benzyl-N-2-imidazolyl)]-5-phenyl-barbituric acid
17. 5-(N-octyl-N-phenyl)-5-phenyl-barbituric acid
18. 5-[N-(2-naphthyl)-N-propyl]-5-phenyl-barbituric acid
19. 5-[N-(4-tetrahydroquinolinyl)-N-propyl]-5-phenyl-barbituric acid
20. 5-[N-benzyl-N-(2-thiophenyl)]-5-phenyl-barbituric acid
21. 5-[N-(3-methylbutyl)-N-[3-(4-pyridyl)propyl)]-5-phenyl-barbituric acid
22. 5-[N-(7-methyloctyl)-N-[3-(2-pyridyl)propyl)]-5-phenyl-barbituric acid
23. 5-(N-(2-hydroxyhexyl)-N-[3-(3-pyridyl)propyl])-5-phenyl-barbituric acid
24. 5-(N-benzyl-N-hexanoyl)-5-phenyl-barbituric acid
25. 5-(N-benzyl-N-octanoyl)-5-phenyl-barbituric acid
26. 5-(N-benzyl-N-octanesulfonyl)-5-phenyl-barbituric acid
27. 5-[N-butyl-N-(2-naphthylsulfonyl)]-5-phenyl-barbituric acid
28. 5-(N-hexyloxycarbonyl-N-propyl)-5-phenyl-barbituric acid
29. 5-(N-(4-methoxy-phenylsulfonyl)-N-hexyl]-5-phenyl-barbituric acid
30. 5-[N-(4-butoxy-phenylsulfonyl)]-N-hexyl]-5-phenyl-barbituric acid
31. 5-[N-benzyl-N-(2-phenethyl)]-5-(4-pyridyl)barbituric acid
32. 5-[N-benzyl-N-(2-phenethyl)]-5-(2-pyridyl)barbituric acid
33. 5-(N,N-dipentyl)-5-(4-piperidinyl)barbituric acid
34. 5-(N,N-dioctyl)-5-(2-thiophenyl)barbituric acid
35. 5-(N-benzyl-N-[2-(2-pyridyl)ethyl]-5-(3-imidazolyl)barbituric acid
36. 5-[1-(4-hydroxy)piperidinyl]-5-(4-pyridyl)barbituric acid
37. 5-[1-(4-hydroxy)piperidinyl]-5-(3-pyridyl)barbituric acid
38. 5-[1-(4-hydroxy)piperidinyl]-5-(2-pyridyl)barbituric acid
39. 5-[1-(4-hydroxy)piperidinyl]-5-(4-piperidinyl)barbituric acid
40. 5-[1-(4-hydroxy)piperidinyl]-5-(2-thiophenyl)barbituric acid
41. 5-[1-(4-hydroxy)piperidinyl]-5-(4-imidazolyl)barbituric acid
42. 5-benzyl-5-[1-(4-hydroxy)piperidinyl]barbituric acid
43. 5-[1-(4-hydroxy)piperidinyl]-5-(2-phenethyl)barbituric acid
44. 5-[1-(4-hydroxy)piperidinyl]-5-(1-naphthyl)barbituric acid
45. 5-[1-(4-hydroxy)piperidinyl]-5-(2-naphthyl)barbituric acid
46. 5-(2-quinolinyl)-5-[1-(4-hydroxy)piperidinyl]barbituric acid
47. 5-[1-(4-hydroxy)piperidinyl]-5-(1-isoquinolinyl)barbituric acid
48. 5-[1-(4-hydroxy)piperidinyl]-5-(2-tetrahydro-quinolinyl)barbituric acid
49. 5-(2-indolyl-5-[1-(4-hydroxy)piperidinyl]barbituric acid
50. 5-(2-benzimidazolyl)-5-[1-(4-hydroxy)piperidinyl]barbituric acid
51. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-octyl-barbituric acid
52. 5-decyl-5-(1-[4-(2-hydroxyethyl)piperazinyl])barbituric acid
53. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-undecyl-barbituric acid
54. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(7-methyl-octyl)barbituric acid
55. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(8-hydroxy-octyl)barbituric acid
56. 5-(8-aminooctyl)-5-(1-[4-(2-hydroxyethyl)piperazinyl])barbituric acid
57. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(2-phen-ethyl)barbituric acid
58. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(4-phenyl-butyl)barbituric acid
59. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(6-phenyl-hexyl)barbituric acid
60. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-[6-(4-methylphenyl)hexyl]barbituric acid
61. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(2-pyridylmethyl)barbituric acid
62. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(4-imidazolylmethyl)barbituric acid
63. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(1-imidazolylmethyl)barbituric acid
64. 5-phenyl-5-(1-(4-propyl)piperazinyl]barbituric acid
65. 5-phenyl-5-(1-tetrahydroquinolinyl)barbituric acid
66. 5-phenyl-5-(1-tetrahydroisoquinolinyl)barbituric acid
67. 5-phenyl-5-[2-(1,2,3,4-tetrahydrobenzo(g)iso-quinolinyl]barbituric acid
68. 5-[2-(2-aza-bicyclo[9.4.0]pentadecyl)]-5-phenyl-barbituric acid
69. 5-[2-(2,11-diaza-12-oxo-bicyclo[9.4.0]pentadecyl)]-5-phenyl-barbituric acid
70. 5-(1-[4-(1-oxo-propyl)]piperidinyl)-5-phenyl-barbituric acid
71. 5-[1-(3-oxo-4-propyl)]piperidinyl]-5-phenyl-barbituric acid
72. 5-phenyl-5-[1-(4-propyl)piperazinyl]barbituric acid
73. 5-[1-(3,5-dihydroxy-4-propyl)piperidinyl]-5-phenyl-barbituric acid
74. 5-(4-chlorophenyl)-5-[1-(4-hydroxy)piperidinyl]barbituric acid
75. 5-(4-chlorobenzyl)-5-[1-(4-hydroxy)piperidinyl]barbituric acid
76. 5-[1-(4-hydroxy)piperidinyl]-5-(4-methoxybenzyl)barbituric acid
77. 3-methyl-5-[1-(4-hydroxy)piperidinyl]-5-phenyl-barbituric acid
78. 1-isopropyl-5-[1-(4-hydroxy)piperidinyl]-5-phenyl-barbituric acid
79. 3-acetyl-5-[1-(4-hydroxy)piperidinyl]-5-phenyl-barbituric acid
80. 5-[1-(4-methoxy)piperidinyl]-5-phenyl-2-thio-barbituric acid
81. 2-imino-5-[1-(4-methoxy)piperidinyl]-5-phenyl-barbituric acid
82. 5-[1-(4-methoxy)piperidinyl]-5-phenyl-2,4,6-triimino-barbituric acid
83. 4,6-diimino-5-[1-(4-methoxy)piperidinyl]-5-phenyl-barbituric acid
84. 5-[1-(4-methoxy)piperidinyl]-5-phenyl-2,4,6-trithio-barbituric acid
85. 5-(6-aminohexyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
86. 5-(6-formylaminohexyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
87. 5-(6-acetylaminohexyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
88. 5-[7-ethoxycarbonyl)heptyl]-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
89. 5-(8-hydroxyoctyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
90. 5-(7-carboxyheptyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
91. 5-[(7-aminocarbonyl)heptyl]-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
92. 5-[3-((aminocarbonylmethyl)aminocarbonyl)propyl]-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
93. 5-[6-(methylamino)hexyl]-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid
94. 5-[4-(n-propyloxy)butyl]-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid
95. 5-[2-(2-(2-methoxyethoxy)ethoxy)ethyl]-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid
96. 5-[2-(2-(ethoxy)ethoxy)ethyl]-5-[N-4-nitrophenyl)piperazinyl]barbituric acid
97. 5-decyl-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid
98. 5-octyl-5-[N-(4-(hydroxysulphonyl)phenyl)piperazinyl]barbituric acid
99. 5-octyl-5-[N-(4-(aminosulphonyl)phenyl)piperazinyl]barbituric acid
100. 5-octyl-5-[N-(4-cyanophenyl)piperazinyl]barbituric acid
101. 5-octyl-5-[N-(4-carboxyphenyl)piperazinyl]barbituric acid
102. 5-octyl-5-[N-(4-(buthoxycarbonyl)phenyl)piperazinyl]barbituric acid
103. 5-octyl-5-[N-(4-(amidino)phenyl)piperazinyl]barbituric acid
104. 5-octyl-5-[N-(4-(aminothiocarbonyl)phenyl)piperazinyl]barbituric acid
105. 5-octyl-5-[N-(4-(methylsulphonyl)phenyl)piperazinyl]barbituric acid
106. 5-octyl-5-[N-(4-(aminocarbonyl)phenyl)piperazinyl]barbituric acid
107. 5-octyl-5-[N-(4-(methylcarbonyl)phenyl)piperazinyl]barbituric acid
108. 5-octyl-5-[N-(4-(dimethylphosphonyl)phenyl)piperazinyl]barbituric acid
109. 5-octyl-5-[N-(4-(amino)phenyl)piperazinyl]barbituric acid
110. 5-octyl-5-[N-(4-acetylamino)phenyl)piperazinyl]barbituric acid
111. 5-octyl-5-[N-(4-trifluoroacetylamino)phenyl)piperazinyl]barbituric acid
112. 5-octyl-5-[N-(4-(methylsulphonylamino)phenyl)piperazinyl]barbituric acid
113. 5-octyl-5-[N-(5-nitropyrid-2-yl)piperazinyl]barbituric acid
114. 5-octyl-5-[N-(N-oxypyrid-4-yl)piperazinyl]barbituric acid
115. 5-octyl-5-[N-(4-(5-triazoIyl)phenyl)piperazinyl]barbituric acid
116. 5-octyl-5-[(N-benzoyl-N-benzyl)amino]barbituric acid
117. 5-[4-(phenyl)phenyl]-5-[(N-benzoyl-N-benzyl)amino]barbituric acid
118. 5-(4-[4-Nitrophenyl)piperazinyl])-5-octyl-barbituric acid
119. N-Benzyl-3-(4-nitro-phenyl)-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)-acrylamide
120. N-Benzyl-2-(3-bromo-phenyl)-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)-acetamide